Identification

Name
Ambenonium
Accession Number
DB01122  (APRD00771)
Type
Small Molecule
Groups
Approved
Description

Ambenonium is a cholinesterase inhibitor used in the management of myasthenia gravis. [Wikipedia]

Structure
Thumb
Synonyms
  • Ambenonium
  • Ambenonium base
  • Ambenonum
Product Ingredients
IngredientUNIICASInChI Key
Ambenonium chloride51FOB87G3I115-79-7DXUUXWKFVDVHIK-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MytelaseTablet10 mg/1OralSanofi Aventis1971-09-082013-03-31Us
International/Other Brands
Mysuran / Mytelase
Categories
UNII
L16PUN799N
CAS number
7648-98-8
Weight
Average: 537.565
Monoisotopic: 536.268482022
Chemical Formula
C28H42Cl2N4O2
InChI Key
OMHBPUNFVFNHJK-UHFFFAOYSA-P
InChI
InChI=1S/C28H40Cl2N4O2/c1-5-33(6-2,21-23-13-9-11-15-25(23)29)19-17-31-27(35)28(36)32-18-20-34(7-3,8-4)22-24-14-10-12-16-26(24)30/h9-16H,5-8,17-22H2,1-4H3/p+2
IUPAC Name
[(2-chlorophenyl)methyl](2-{[(2-{[(2-chlorophenyl)methyl]diethylazaniumyl}ethyl)carbamoyl]formamido}ethyl)diethylazanium
SMILES
CC[N+](CC)(CCNC(=O)C(=O)NCC[N+](CC)(CC)CC1=CC=CC=C1Cl)CC1=CC=CC=C1Cl

Pharmacology

Indication

Ambenonium is used to treat muscle weakness due to muscle disease (myasthenia gravis).

Pharmacodynamics

Ambenonium, similar to pyridostigmine and neostigmine, is used for the treatment of muscle weakness and fatigue in people with myasthenia gravis. It is postulated to exert its therapeutic effect by enhancing cholinergic function through the inhibition of the acetylcholine hydrolysis by acetylcholinesterase. Increased levels of acetylcholine has peripheral effects, as acetylcholine is also used in the brain, where it tends to cause excitatory actions. The glands that receive impulses from the parasympathetic part of the autonomic nervous system are also stimulated in the same way. This is why an increase in acetylcholine causes a decreased heart rate and increased production of saliva. Ambenonium is used less commonly than neostigmine or pyridostigmine but may be preferred in patients hypersensitive to the bromide ion. Ambenonium produces fewer muscarinic side effects than neostigmine, but more than pyridostigmine.

Mechanism of action

Ambenonium exerts its actions against myasthenia gravis by competitive, reversible inhibition of acetylcholinesterase. The disease myasthenia gravis occurs when the body inappropriately produces antibodies against acetylcholine receptors, and thus inhibits proper acetylcholine signal transmission (when acetylcholine binds to acetylcholine receptors of striated muscle fibers, it stimulates those fibers to contract). Ambenonium reversibly binds acetylcholinesterase at the anionic site, which results in the blockage of the site of acetycholine binding, thereby inhibiting acetylcholine hydrolysis and enhancing cholinergic function through the accumulation of acetycholine at cholinergic synpases. In turn this facilitates transmission of impulses across the myoneural junction and effectively treats the disease.

TargetActionsOrganism
AAcetylcholinesterase
inhibitor
Human
Absorption

Oral - poorly absorbed from the gastrointestinal tract.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Plasma and hepatic

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

LD50=150±44 mg/kg (orally in mice). Symptoms of overdose include muscle twitching, weakness and paralysis of voluntary muscles including the tongue, shoulders, neck and arms, blood pressure increase (with or without a slowing of heart rate), a sensation of internal trembling, severe anxiety, and panic. Death may occur rapidly if untreated.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
16-BromoepiandrosteroneThe risk or severity of adverse effects can be increased when 16-Bromoepiandrosterone is combined with Ambenonium.
19-norandrostenedioneThe risk or severity of adverse effects can be increased when 19-norandrostenedione is combined with Ambenonium.
5-androstenedioneThe risk or severity of adverse effects can be increased when 5-androstenedione is combined with Ambenonium.
AcebutololAmbenonium may increase the bradycardic activities of Acebutolol.
AcetylcholineThe risk or severity of adverse effects can be increased when Ambenonium is combined with Acetylcholine.
AclidiniumThe therapeutic efficacy of Aclidinium can be decreased when used in combination with Ambenonium.
AgmatineThe therapeutic efficacy of Agmatine can be decreased when used in combination with Ambenonium.
AlclometasoneThe therapeutic efficacy of Ambenonium can be decreased when used in combination with Alclometasone.
AlcuroniumThe therapeutic efficacy of Alcuronium can be decreased when used in combination with Ambenonium.
AldosteroneThe risk or severity of adverse effects can be increased when Aldosterone is combined with Ambenonium.
Food Interactions
Not Available

References

Synthesis Reference

Kirchner, F.K.; U.S. Patent 3,096,373; July 2,1963; assigned to Sterling Drug Inc.

General References
Not Available
External Links
Human Metabolome Database
HMDB0015254
KEGG Compound
C07773
PubChem Compound
2131
PubChem Substance
46508143
ChemSpider
2046
BindingDB
50262988
ChEBI
2627
ChEMBL
CHEMBL1652
Therapeutic Targets Database
DAP000893
PharmGKB
PA164764601
Drugs.com
Drugs.com Drug Page
Wikipedia
Ambenonium
ATC Codes
N07AA30 — Ambenonium
MSDS
Download (166 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Bayer Healthcare
  • Sanofi-Aventis Inc.
Dosage forms
FormRouteStrength
TabletOral10 mg/1
Prices
Unit descriptionCostUnit
Mytelase 10 mg caplet1.86USD caplet
Mytelase 10 mg tablet1.86USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)196-199 °CKirchner, F.K.; U.S. Patent 3,096,373; July 2,1963; assigned to Sterling Drug Inc.
water solubilitySolubleNot Available
Predicted Properties
PropertyValueSource
Water Solubility9.42e-07 mg/mLALOGPS
logP2.27ALOGPS
logP-3.6ChemAxon
logS-8.8ALOGPS
pKa (Strongest Acidic)10.78ChemAxon
pKa (Strongest Basic)-3.6ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area58.2 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity173.57 m3·mol-1ChemAxon
Polarizability59.98 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9618
Blood Brain Barrier+0.8373
Caco-2 permeable+0.5168
P-glycoprotein substrateSubstrate0.8725
P-glycoprotein inhibitor INon-inhibitor0.6717
P-glycoprotein inhibitor IINon-inhibitor0.766
Renal organic cation transporterNon-inhibitor0.823
CYP450 2C9 substrateNon-substrate0.7865
CYP450 2D6 substrateNon-substrate0.7008
CYP450 3A4 substrateSubstrate0.5842
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.6899
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8308
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.538
Ames testNon AMES toxic0.7312
CarcinogenicityNon-carcinogens0.6118
BiodegradationNot ready biodegradable0.9927
Rat acute toxicity2.4379 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9665
hERG inhibition (predictor II)Inhibitor0.8507
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as alpha amino acid amides. These are amide derivatives of alpha amino acids.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acid amides
Alternative Parents
Phenylmethylamines / Benzylamines / Chlorobenzenes / Aralkylamines / Aryl chlorides / Tetraalkylammonium salts / Secondary carboxylic acid amides / Organopnictogen compounds / Organochlorides / Organic salts
show 4 more
Substituents
Alpha-amino acid amide / Benzylamine / Phenylmethylamine / Aralkylamine / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid
show 18 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
quaternary ammonium ion (CHEBI:2627)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine hydrolase activity
Specific Function
Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.
Gene Name
ACHE
Uniprot ID
P22303
Uniprot Name
Acetylcholinesterase
Molecular Weight
67795.525 Da
References
  1. Lockhart B, Closier M, Howard K, Steward C, Lestage P: Differential inhibition of [3H]-oxotremorine-M and [3H]-quinuclinidyl benzilate binding to muscarinic receptors in rat brain membranes with acetylcholinesterase inhibitors. Naunyn Schmiedebergs Arch Pharmacol. 2001 Apr;363(4):429-38. [PubMed:11330337]
  2. Hodge AS, Humphrey DR, Rosenberry TL: Ambenonium is a rapidly reversible noncovalent inhibitor of acetylcholinesterase, with one of the highest known affinities. Mol Pharmacol. 1992 May;41(5):937-42. [PubMed:1588924]
  3. Papp MI, Komoly S, Szirmai IG, Kovacs T: Similarities between CSF-brain extracellular transfer and neurofibrillary tangle invasion in Alzheimer's disease. Neurobiol Aging. 2006 Mar;27(3):402-12. Epub 2005 Jun 27. [PubMed:15982786]
  4. Kenakin TP, Beek D: Self-cancellation of drug properties as a mode of organ selectivity: the antimuscarinic effects of ambenonium. J Pharmacol Exp Ther. 1985 Mar;232(3):732-40. [PubMed:2857786]
  5. Webb GD: Affinity of benzoquinonium and ambenonium derivatives for the acetylcholine receptor, tested on the electroplax, and for acetylcholinesterase in solution. Biochim Biophys Acta. 1965 May 25;102(1):172-84. [PubMed:5833399]
  6. Bolognesi ML, Cavalli A, Andrisano V, Bartolini M, Banzi R, Antonello A, Rosini M, Melchiorre C: Design, synthesis and biological evaluation of ambenonium derivatives as AChE inhibitors. Farmaco. 2003 Sep;58(9):917-28. [PubMed:13679187]
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. Yamamoto K, Kohda Y, Sawada Y, Iga T: Pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats. Biopharm Drug Dispos. 1991 Nov;12(8):613-25. [PubMed:1801966]

Drug created on June 13, 2005 07:24 / Updated on October 01, 2018 16:36